Translocations involving ETS family proteins in human cancer

Abstract

The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating certain gene transcriptions. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. Three chimeric genes involving ETS genes have been identified in human cancers, which are EWS-FLI1 in Ewing's sarcoma, TMPRSS2-ERG in prostate cancer, and ETV6-RUNX1 in acute lymphocytic leukemia. Although these fusion transcripts definitely contribute to the pathogenesis of the disease, the impact of these fusion transcripts on patients' prognosis is highly controversial. In the present review, the roles of ETS protein translocations in human carcinogenesis are discussed.

Keywords: ERG; ETS; ETV6; EWS; FLI1; RUNX1 expression; TMPRSS2; cancer.

Figure 1.. The structure of ETS family proteins

The structure of ETS family proteins. The human ETS factors are classified into 11 subgroups: ETS (ETS1/2), ERG, FLI1, ETV (PEA3, ETV1/4/5), TEL (ETV6/7), ELG (GABPα), TCF (ELK1/3/4), ELF (ELF1/2/4), SPI1 (SPI1/B/C), ERF (ERF, ETV3, ETV3L), and FEV [4, 5, 165, 166]. There are totally 28 ETS proteins in humans. ETS translocations involving Fli1, ERG, and TEL have been discussed in this review. The ETS domain that is essential for DNA-binding is shown in dark box. The DNA-binding by the ternary complex factor (TCF) subfamily of ETS-domain transcription factors is tightly regulated by intramolecular and intermolecular interactions [167]. The helix-loop-helix (HLH) - containing Id proteins are trans-acting negative regulators of DNA binding by the TCFs. Id domains have been identified in ETS, ETV, and TCF. PNT: pointed domain, TAD: transactivation domain, Id: Id-interaction domain, ETS: ETS domain (DNA-binding domain), RD: ring domain.

Figure 2.. The EWS-FlI1 chimeric gene found in Ewing’s sarcomas

The EWS-FlI1 chimeric gene is found in 80% of Ewing sarcomas. Vertical arrow shows the major breakpoints (between exon 7 and 8 in EWS gene and exons 5 and 6 in ETS-like FLI1 gene). The thin arrows represent the minor breakpoints. The EWS-FLI1 gene is a fusion between EWS and FLI1, transactivation (EWS) and DNA-binding (FLI1) domains. The structure between EWS and FLI1 varies dependent on the Ewing’s sarcoma.

Figure 3.. The TMPRSS2-ERG gene found in prostate cancer

The TMPRSS2-ERG or ETV chimeric gene has been found in ~80% of prostate cancer samples of radical prostatectomy [81]. The former translocation has been found in ~50% of Caucasians, with a lower frequency in African Americans, and even less common in Asians [83]. The structure of chromosome of 21 where the chimeric gene for TMPRSS2-ERG is derived is shown. Most of the resultant TMPRSS2-ERG gene consists of exon 1 of TMPRSS2 (non-coding) and exons 4–11 of ERG indicating that the gene makes near full-length proteins of ERG consistent with ERG overexpression in PCa. On the other hand, the TMPRSS2-ETV1 fusion results in chimeric protein that consists with a part of TMPRSS2 and truncated form of ETV1, resulting in expression of the fusion protein that is not expressed in normal tissues.

Figure 4.. The genomic DNA structure for the TEL-AML1 (ETV6-RUNX1) locus

Translocations involving these loci are found in 25% of pediatric ALL, and are associated with relatively favorable prognosis. The TEL (ETV6) gene is chromosome 12p13, and the AML1 (RUNX1) gene is located on chromosome 21q22. The shaded boxes indicate the locations of breakpoints found in ALL. The numbers are the positions of exons. The information on breakpoints comes from references and . The intron 2 in reference is intron 1 in reference .